The time between the onset of disease in a patient and the conclusion of a successful course of therapy is often unacceptably long. Many diseases remain asymptomatic and evade detection while progressing to advanced, and often terminal, stages. In addition, this period may be marked by significant psychological and physical trauma for the patient due to the unpleasant side effects of even correctly prescribed treatments. Even diseases that are detected early may be most effectively treated only by therapies that disrupt the normal functions of healthy tissue or have other unwanted side effects.
One such disease is cancer. Despite considerable research effort and some success, cancer is still the second leading cause of death in the United States, claiming more than 500,000 lives each year according to American Cancer Society estimates. Traditional treatments are invasive and/or are attended by harmful side effects (e.g., toxicity to healthy cells), often making for a traumatic course of therapy with only modest success. Early detection, a result of better diagnostic practices and technology, has improved the prognosis for many patients. However, the suffering that many patients must endure makes for a more stressful course of therapy and may complicate patient compliance with prescribed therapies. Further, some cancers defy currently available treatment options, despite improvements in disease detection. Of the many forms of cancer that still pose a medical challenge, prostate, breast, lung, and liver claim the vast majority of lives each year. Colorectal cancer, ovarian cancer, gastric cancer, leukemia, lymphoma, melanoma, and their metastases may also be life threatening.
Conventional treatments for breast cancer, for example, typically include surgery followed by radiation and/or chemotherapy. These techniques are not always effective, and even if effective, they suffer from certain deficiencies. Surgical procedures range from removal of only the tumor (lumpectomy) to complete removal of the breast. In early stage cancer, complete removal of the breast may provide an assurance against recurrence, but is disfiguring and requires the patient to make a very difficult choice. Lumpectomy is less disfiguring, but can be associated with a greater risk of cancer recurrence. Radiation therapy and chemotherapy are arduous and are not completely effective against recurrence.
Treatment of pathogen-based diseases is also not without complications. Patients presenting symptoms of systemic infection are often mistakenly treated with broad-spectrum antibiotics as a first step. This course of action is completely ineffective when the invading organism is viral. Even if a bacterium (e.g., E. coli) is the culprit, the antibiotic therapy eliminates not only the offending bacteria, but also benign intestinal flora in the gut that are necessary for proper digestion of food. Hence, patients treated in this manner often experience gastrointestinal distress until the benign bacteria can repopulate. In other instances, antibiotic-resistant bacteria may not respond to antibiotic treatment. Therapies for viral diseases often target only the invading viruses themselves. However, the cells that the viruses have invaded and “hijacked” for use in making additional copies of the virus remain viable. Hence, progression of the disease is delayed, rather than halted.
For these reasons, it was desirable to provide improved and alternative techniques for treating disease, particularly techniques that are less invasive and traumatic to the patient than the existing techniques, and effective only locally at targeted sites, such as diseased tissue, pathogens, or other undesirable matter in the body. It was also desirable to provide techniques capable of being performed in a single or very few treatment sessions (minimizing patient non-compliance), with minimal toxicity to the patient, and which could be targeted to the diseased tissues without requiring significant operator skill and input.
One such alternative technique is immunotherapy, which is a rapidly expanding type of therapy used for treating a variety of human diseases including cancer, for example. The FDA has approved a number of antibody-based cancer therapeutics. The ability to engineer antibodies, antibody fragments, and peptides with altered properties (e.g., antigen binding affinity, molecular architecture, specificity, valence, etc.) has enhanced their use in therapies. Cancer immunotherapeutics have made use of advances in the chimerization and humanization of murine antibodies to reduce immunogenic responses in humans. High affinity human antibodies have also been obtained from transgenic animals that contain many human immunoglobulin genes. In addition, phage display technology, ribosome display, and DNA shuffling have allowed for the discovery of antibody fragments and peptides with high affinity and low immunogenicity for use as targeting ligands. All of these advances have made it possible to design an immunotherapy that has a desired antigen binding affinity and specificity, and minimal immune response.
The field of cancer immunotherapy makes use of markers that are over-expressed by cancer cells (relative to normal cells) or expressed only by cancer cells. The identification of such markers is ongoing and the choice of a ligand/marker combination is critical to the success of any immunotherapy. Immunotherapeutics fall into at least three classes: (1) deployment of antibodies that, themselves, target growth receptors, disrupt cytokine pathways, or induce complement or antibody-dependent cytotoxicity; (2) direct arming of antibodies with a toxin, a radionuclide, or a cytokine; (3) indirect arming of antibodies by attaching them to immunoliposomes used to deliver a toxin or by attaching them to an immunological cell effector (bispecific antibodies). Although armed antibodies have shown potent tumor activity in clinical trials, they have also exhibited unacceptably high levels of toxicity to patients.
The disadvantage of therapies that rely on delivery of immunotoxins or radionuclides (i.e., direct and indirect arming) has been that, once administered to the patient, these agents are active at all times. These therapies often cause damage to non-tumor cells and present toxicity issues and delivery challenges. For example, cancer cells commonly shed surface-expressed antigens (targeted by immunotherapeutics) into the blood stream. Immune complexes can be formed between the immunotherapeutic and the shed antigen. As a result, many antibody-based therapies are diluted due to the interaction of the antibody with these shed antigens rather than interacting with the cancer cells, and thereby reducing the true delivered dose. Thus, a “therapy-on-demand” approach that minimizes adverse side effects and improves efficacy would be preferable.
With thermotherapy, temperatures in a range from about 40° C. to about 46° C. (hyperthermia) can cause irreversible damage to disease cells. However, healthy cells are capable of surviving exposure to temperatures up to around 46.5° C. Elevating the temperature of individual cells in diseased tissue to a lethal level (cellular thermotherapy) may provide a superior treatment option. Pathogens implicated in disease and other undesirable matter in the body can also be destroyed via exposure to locally high temperatures.
Temperatures greater than 46° C. may also be effective for the treatment of cancer and other diseases by causing an instantaneous thermo-ablative response. However, accurate and precise targeting is necessary to ensure that a minimal amount of healthy tissue is exposed to such temperatures. Failure to achieve such a level of targeting may produce increased detrimental side effects, and thereby reducing the benefits of the treatment.
Hyperthermia may hold promise as a treatment for cancer and other diseases because it induces instantaneous necrosis (typically referred to as “thermo-ablation”) and/or a heat-shock response in cells (classical hyperthermia), leading to cell death via a series of biochemical changes within the cell. State-of-the-art systems that employ microwave or radio frequency (RF) hyperthermia, such as annular phased array systems (APAS), attempt to tune energy for regional heating of deep-seated tumors. Such techniques are limited by the heterogeneities of tissue electrical conductivities and that of highly perfused tissue. This leads to the as-yet-unsolved problems of “hot spot” phenomena in untargeted tissue with concomitant under-dosage in the desired areas. The result is often a lower than expected therapeutic ratio, and an inherent difficulty to determine with adequate precision the heat dose delivered to the desired area. The latter precludes the development of prescriptive clinical protocols, which are necessary to ensure reproducible and predictable patient benefits following treatment. All of these factors make selective heating of specific regions with such systems very difficult.
Another strategy that utilizes RF hyperthermia requires surgical implantation of microwave or RF based antennae or self-regulating thermal seeds. While this approach avoids problems related to dose determination and some of the problems associated with targeting, it requires an invasive procedure to implant the thermal seeds. In addition to its invasiveness, this approach provides few (if any) options for treatment of metastases because it requires knowledge of the precise location of the primary tumor. The seed implantation strategy is thus incapable of targeting undetected individual cancer cells or cell clusters not immediately adjacent to the primary tumor site. Clinical success of this strategy is hampered by problems with the targeted generation of heat at the desired tumor tissues.
A strategy for treating a disease by generating heat within a tumor using superparamagnetic particles (having characteristic relaxation time≈10−9 sec) that are suspended in a suitable medium, referred to as magnetic fluids, and exposing the patient to an alternating magnetic field (AMF) has been proposed (see e.g., U.S. Pat. No. 6,541,039 to Lesniak et al. and U.S. Pat. No. 6,470,220 to Kraus, et al.). While some variations exist, generally the methods disclosed in the prior art involve the introduction of the magnetic fluid directly into the region to be treated and heating the particles by exposing a significant portion of the patient to low amplitude (less than 16 kA/m) alternating magnetic fields with frequency of between 50 kHz and 200 kHz, including the region of interest. It is well established that exposing a significant portion of a patient to an AMF will increase tissue temperature over the whole region exposed, and even the core body temperature, significantly because of the eddy currents generated by the interaction of the AMF with tissues. Indeed, this is the general strategy used with antennae-based or annular phased array RF devices described above. A cancer tumor located within this region would thus experience an elevated temperature even without a magnetic fluid. Tumor temperature increases to a range of about 40° C. to 43° C. are reported in some cases. Such tumor temperatures seem low when one considers the relatively large amounts, about 10 mg to 100 mg particles per gram of tumor, of superparamagnetic particles injected directly into the tumor. This suggests that a significant portion of the heat is the result of direct AMF effects on tissue (eddy current), with a lesser degree of heat contributed by the presence of the particles.
The magnetic fluids as described comprise non-interacting superparamagnetic particles, which are stated to be preferred because of their decreased tendency to aggregate. Because the magnetic particles comprising the fluid are superparamagnetic, viscous heating is the mechanism giving rise to particle rotation that deposits energy into the medium due to its viscosity, i.e., Brownian relaxation. As disclosed in the prior art, superparamagnetic particles are preferred because they will have zero, or near zero, remanence, and thus a reduced tendency to aggregate, which occurs when their magnetic moments are non-interacting. Heating via Neél relaxation (magnetic hysteresis) is precluded in this instance, unless the AMF period is significantly shorter (less than 10−9 sec) than the characteristic relaxation time of the particle magnetic moments. Thus, magnetic hysteresis heating with an AMF is only possible if the AMF frequency is greater than 1 GHz. For methods involving the compositions of the magnetic (superparamagnetic) fluids described, and the typical AMF frequencies disclosed therein (about 100 kHz), there is no possible contribution of heating via Neél relaxation.